Artikel
Rheumatoid arthritis synovial fibroblast and endothelial cell interaction are altered by activin/follistatin
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Autoren
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Elena Neumann
- Rheumatologie und Klinische Immunologie, Justus Liebig Universität Gießen, Campus Kerckhoff, Bad Nauheim
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Helge Scholz
- Rheumatologie und Klinische Immunologie, Justus Liebig Universität Gießen, Campus Kerckhoff, Bad Nauheim
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Iris Aykara
- Rheumatologie und Klinische Immunologie, Justus Liebig Universität Gießen, Campus Kerckhoff, Bad Nauheim
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Klaus Frommer
- Rheumatologie und Klinische Immunologie, Justus Liebig Universität Gießen, Campus Kerckhoff, Bad Nauheim
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Stefan Rehart
- Klinik für Orthopädie und Unfallchirurgie, Agaplesion Markus Krankenhaus, Frankfurt am Main
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Ulf Müller-Ladner
- Rheumatologie und Klinische Immunologie, Justus Liebig Universität Gießen, Campus Kerckhoff, Bad Nauheim
| Veröffentlicht: | 14. September 2021 |
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Gliederung
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Introduction: Activin A and follistatin belong to an anti-inflammatory auto-regulatory cycle. Rheumatoid arthritis (RA) patients have increased activin A levels in synovial fluid and tissue. During inflammation, activin A is released, then inducing its antagonist follistatin. This cycle is active in endothelial cells (EC) but not RA synovial fibroblasts (SF). Fibroblasts interact with EC inducing angiogenesis. Therefore, the role of activin/follistatin in RASF/EC interactions was evaluated.
Methods: RASF and HUVEC were stimulated in mono- and coculture. Direct: RASF with HUVEC 1:1. Indirect: HUVEC in inserts, RASF in lower chambers. Stimuli: activin A 15ng/ml, follistatin 500ng/ml, IL-1 1ng/ml. Short-term adhesion: Calcein-AM-stained RASF on confluent HUVEC for 1h. Flow-adhesion assay: HUVEC cultured on capillary slides stimulated with TNF, TNF/activin or TNF/follistatin. TNF-stimulated RASF were sent through the capillaries. Migration assay: 2% FCS medium with RASF in inserts placed into wells with 10% FCS, stimulation 16h with IL-1, IL-1/activin or IL-1/follistatin. Scratch-assay: After stimulation scratches were recorded over time.
Results: IL-1 induced activin A in RASF and HUVEC in all settings. IL-1-induced activin A was reduced by follistatin in HUVEC monoculture and cocultures compared to IL-1 alone but not RASF monoculture. IL-1-induced IL-6 was reduced by activin A in HUVEC and indirect coculture but not RASF monoculture and direct coculture. Follistatin did not change IL-6 release. IL-1 induced VEGF in RASF but was not changed by activin A. Short-term adhesion was not altered by activin A or follistatin (n=4). Flow adhesion showed a reduced adherence/rolling of RASF on TNF and activin A stimulated HUVEC (n=4). IL-1 decreased migration but was not changed by activin A or follistatin. Scratch assays showed increased migration in direct coculture with stronger differences between stimulated and unstimulated RASF in monoculture and indirect coculture (n=4).
Conclusion: Activin A alters selectin-mediated adhesion under flow conditions. IL-1-induced effects on cell migration were enhanced by activin A promoting the IL-1-induced migration decrease in indirect coculture and RASF monoculture although cell motility was highest in direct coculture. In direct and indirect coculture, the HUVEC effect was dominant leading to reduced IL-1-induced activin A release. The IL-1-induced IL-6 release in RASF or HUVECs was decreased by activin A but not during cell-contact. The direct interaction of RASF with HUVEC seems to prevent the anti-inflammatory activin A effect on HUVECs.
Disclosures: Nicht erforderlich
